SARS-CoV-2, the other face to SARS-CoV and MERS-CoV: Future predictions.

Coronavirus disease 2019 (COVID-19) outbreak is proving to be an unprecedented disaster that lays its dark shadow on global health, economics and personal freedom. Severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) epidemics provide scientific data that is useful in better understanding and resolution of COVID-19. Similarities among SARS-CoV, MERS-CoV and SARS-CoV-2 have been investigated in the light of available data. SARS-CoV, MERS-CoV and SARS-CoV-2 evolved in bats and have positive-sense RNA genomes of 27.9 kb, 30.1 kb and 29.9 kb, respectively. Molecular and serological tools used for diagnosis of SARS and MERS patients resemble COVID-19 diagnostic tools. Stability and longevity data of SARS and MERS epidemics contribute in the current pandemic precaution policies. Trials to produce vaccines for SARS-CoV and MERS-CoV failed, therefore different strategies were employed for SARS-CoV2 vaccines production and during the past period antiviral agents, Convalescent plasma and monoclonal antibodies provide potential treatments for sever patients. The mortality rate caused by the SARS-CoV and MERS-CoV reached 15% and 37%, respectively. The first declarations about mortality rate of SARS-CoV-2 was around 2-4% but now this rate differed globally and reached more than 13% in some countries. A realistic COVID-19 outbreak scenario suggest that the pandemic might last for three years with fluctuation in the number of infected cases, unless vaccination process goes faster and/or antiviral drug is discovered.

Comparison of acute pneumonia caused by SARS-COV-2 and other respiratory viruses in children: a retrospective multi-center cohort study during COVID-19 outbreak.

BACKGROUND: Until January 18, 2021, coronavirus disease-2019 (COVID-19) has infected more than 93 million individuals and has caused a certain degree of panic. Viral pneumonia caused by common viruses such as respiratory syncytial virus, rhinovirus, human metapneumovirus, human bocavirus, and parainfluenza viruses have been more common in children. However, the incidence of COVID-19 in children was significantly lower than that in adults. The purpose of this study was to describe the clinical manifestations, treatment and outcomes of COVID-19 in children compared with those of other sources of viral pneumonia diagnosed during the COVID-19 outbreak. METHODS: Children with COVID-19 and viral pneumonia admitted to 20 hospitals were enrolled in this retrospective multi-center cohort study. A total of 64 children with COVID-19 were defined as the COVID-19 cohort, of which 40 children who developed pneumonia were defined as the COVID-19 pneumonia cohort. Another 284 children with pneumonia caused by other viruses were defined as the viral pneumonia cohort. The epidemiologic, clinical, and laboratory findings were compared by Kolmogorov-Smirnov test, t-test, Mann-Whitney U test and Contingency table method. Drug usage, immunotherapy, blood transfusion, and need for oxygen support were collected as the treatment indexes. Mortality, intensive care needs and symptomatic duration were collected as the outcome indicators. RESULTS: Compared with the viral pneumonia cohort, children in the COVID-19 cohort were mostly exposed to family members confirmed to have COVID-19 (53/64 vs. 23/284), were of older median age (6.3 vs. 3.2 years), and had a higher proportion of ground-glass opacity (GGO) on computed tomography (18/40 vs. 0/38, P < 0.001). Children in the COVID-19 pneumonia cohort had a lower proportion of severe cases (1/40 vs. 38/284, P = 0.048), and lower cases with high fever (3/40 vs. 167/284, P < 0.001), requiring intensive care (1/40 vs. 32/284, P < 0.047) and with shorter symptomatic duration (median 5 vs. 8 d, P < 0.001). The proportion of cases with evaluated inflammatory indicators, biochemical indicators related to organ or tissue damage, D-dimer and secondary bacterial infection were lower in the COVID-19 pneumonia cohort than those in the viral pneumonia cohort (P < 0.05). No statistical differences were found in the duration of positive PCR results from pharyngeal swabs in 25 children with COVID-19 who received antiviral drugs (lopinavir-ritonavir, ribavirin, and arbidol) as compared with duration in 39 children without antiviral therapy [median 10 vs. 9 d, P = 0.885]. CONCLUSION: The symptoms and severity of COVID-19 pneumonia in children were no more severe than those in children with other viral pneumonia. Lopinavir-ritonavir, ribavirin and arbidol do not shorten the duration of positive PCR results from pharyngeal swabs in children with COVID-19. During the COVID-19 outbreak, attention also must be given to children with infection by other pathogens infection.

IL-1 Receptor Antagonist Anakinra in the Treatment of COVID-19 Acute Respiratory Distress Syndrome: A Retrospective, Observational Study.

The IL-1 receptor antagonist, anakinra, may represent a therapeutic option for acute respiratory distress syndrome (ARDS) associated with coronavirus disease 2019 (COVID-19). In this study, COVID-19 ARDS patients admitted to the Azienda Socio Sanitaria Territoriale of Lecco, Italy, between March 5th to April 15th, 2020, and who had received anakinra off-label were retrospectively evaluated and compared with a cohort of matched controls who did not receive immunomodulatory treatment. The primary end point was survival at day 28. The population consisted of 112 patients (56 treated with anakinra and 56 controls). Survival at day 28 was obtained in 69 patients (61.6%) and was significantly higher in anakinra-treated patients than in the controls (75.0 versus 48.2%, p = 0.007). When stratified by continuous positive airway pressure support at baseline, anakinra-treated patients' survival was also significant compared with the controls (p = 0.008). Univariate analysis identified anakinra usage (odds ratio, 3.2; 95% confidence interval, 1.47-7.17) as a significant survival predictor. This was not supported by multivariate modeling. The rate of infectious-related adverse events was similar between groups. In conclusion, anakinra improved overall survival and invasive ventilation-free survival and was well tolerated in patients with ARDS associated with COVID-19.

Structural Analysis of Neutralizing Epitopes of the SARS-CoV-2 Spike to Guide Therapy and Vaccine Design Strategies.

Coronavirus research has gained tremendous attention because of the COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus (nCoV or SARS-CoV-2). In this review, we highlight recent studies that provide atomic-resolution structural details important for the development of monoclonal antibodies (mAbs) that can be used therapeutically and prophylactically and for vaccines against SARS-CoV-2. Structural studies with SARS-CoV-2 neutralizing mAbs have revealed a diverse set of binding modes on the spike's receptor-binding domain and N-terminal domain and highlight alternative targets on the spike. We consider this structural work together with mAb effects in vivo to suggest correlations between structure and clinical applications. We also place mAbs against severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses in the context of the SARS-CoV-2 spike to suggest features that may be desirable to design mAbs or vaccines capable of conferring broad protection.

Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody.

The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope that overlaps the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses.

Spatial and temporal roles of SARS-CoV PLpro -A snapshot.

SARS-CoV and SARS-CoV-2 encode four structural and accessory proteins (spike, envelope, membrane and nucleocapsid proteins) and two polyproteins (pp1a and pp1ab). The polyproteins are further cleaved by 3C-like cysteine protease (3CLpro ) and papain-like protease (PLpro ) into 16 nonstructural proteins (nsps). PLpro is released from nsp3 through autocleavage, and then it cleaves the sites between nsp1/2, between nsp2/3 and between nsp3/4 with recognition motif of LXGG, and the sites in the C-terminus of ubiquitin and of protein interferon-stimulated gene 15 (ISG15) with recognition motif of RLRGG. Alone or together with SARS unique domain (SUD), PLpro can stabilize an E3 ubiquitin ligase, the ring-finger, and CHY zinc-finger domain-containing 1 (RCHY1), through domain interaction, and thus, promote RCHY1 to ubiquitinate its target proteins including p53. However, a dilemma appears in terms of PLpro roles. On the one hand, the ubiquitination of p53 is good for SARS-CoV because the ubiquitinated p53 cannot inhibit SARS-CoV replication. On the other hand, the ubiquitination of NF-κB inhibitor (IκBα), TNF receptor-associated factors (TRAFs), and stimulator of interferon gene (STING), and the ISGylation of targeted proteins are bad for SARS-CoV because these ubiquitination and ISGylation initiate the innate immune response and antiviral state. This mini-review analyzes the dilemma and provides a snapshot on how the viral PLpro smartly manages its roles to avoid its simultaneously contradictory actions, which could shed lights on possible strategies to deal with SARS-CoV-2 infections.

Spatial and temporal roles of SARS-CoV PLpro -A snapshot.

SARS-CoV and SARS-CoV-2 encode four structural and accessory proteins (spike, envelope, membrane and nucleocapsid proteins) and two polyproteins (pp1a and pp1ab). The polyproteins are further cleaved by 3C-like cysteine protease (3CLpro ) and papain-like protease (PLpro ) into 16 nonstructural proteins (nsps). PLpro is released from nsp3 through autocleavage, and then it cleaves the sites between nsp1/2, between nsp2/3 and between nsp3/4 with recognition motif of LXGG, and the sites in the C-terminus of ubiquitin and of protein interferon-stimulated gene 15 (ISG15) with recognition motif of RLRGG. Alone or together with SARS unique domain (SUD), PLpro can stabilize an E3 ubiquitin ligase, the ring-finger, and CHY zinc-finger domain-containing 1 (RCHY1), through domain interaction, and thus, promote RCHY1 to ubiquitinate its target proteins including p53. However, a dilemma appears in terms of PLpro roles. On the one hand, the ubiquitination of p53 is good for SARS-CoV because the ubiquitinated p53 cannot inhibit SARS-CoV replication. On the other hand, the ubiquitination of NF-κB inhibitor (IκBα), TNF receptor-associated factors (TRAFs), and stimulator of interferon gene (STING), and the ISGylation of targeted proteins are bad for SARS-CoV because these ubiquitination and ISGylation initiate the innate immune response and antiviral state. This mini-review analyzes the dilemma and provides a snapshot on how the viral PLpro smartly manages its roles to avoid its simultaneously contradictory actions, which could shed lights on possible strategies to deal with SARS-CoV-2 infections.

Distinct phenotypes in COVID-19 may require distinct pulmonary rehabilitation strategies.

The novel coronavirus (SARS-CoV-2) has distinct clinical manifestations that can vary from an asymptomatic condition to severe acute respiratory failure. Phenotypes are attributable to different pathophysiological mechanisms and require different treatment strategies. The assessment and identification of different phenotypes can guide therapy configurations such as oxygen therapy, non-invasive ventilation, airway management, and tracheal intubation. Further studies are essential to provide information on the influence of phenotypes in the decision of rehabilitation strategies. The sequelae left in the respiratory system of COVID-19 survivors and its limitations will be a challenge for rehabilitation services worldwide. Lung injuries are directly related to the phenotypes presented, and depending on the degree of these injuries, rehabilitation strategies can be targeted. We believe that differentiating patients, according to their respective phenotypes, can improve decision-making in treatment and individualized rehabilitation.

Clinical course of COVID-19 among immunocompromised children: a clinical case series.

Infection with SARS-CoV-2 represents a great source of concern and a new threat for immunocompromised patients. Limited studies are available on COVID-19 in immunocompromised children. This case series aimed to evaluate the clinical and laboratory characteristics, management and outcomes of COVID-19 in five children immunocompromised due to different underlying conditions. All had mild symptoms or were asymptomatic at presentation. All had a benign course of illness. No changes or delays in their treatment regimens occurred, and none experienced a relapse of the original disease, developed severe COVID-19 or died. However, these cases showed a prolonged duration of virus shedding. This report suggests that immunocompromised paediatric patients may not be at a higher risk of developing severe COVID-19. However, further studies are required to elaborate on the pathogenesis of COVID-19 in this vulnerable group.

Are there pulmonary sequelae in patients recovering from COVID-19?

It has been recently hypothesized that infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to fibrotic sequelae in patients recovering from coronavirus disease 2019 (COVID-19). In this observational study, hospitalized patients with COVID-19 had a HRCT of the chest performed to detect the extension of fibrotic abnormalities via Hounsfield Units (HU). At follow-up, the lung density significantly improved in both lungs and in each lobe of all patients, being in the normal range (- 950 to - 700 HU). This study provides preliminary evidence that hospitalized patients with mild-to-moderate forms of COVID-19 are not at risk of developing pulmonary fibrosis.

Development of bullous lung disease in a patient with severe COVID-19 pneumonitis.

A 60-year-old man presented with sudden onset right-sided chest pain and gradually worsening shortness of breath on exertion. Eleven days earlier, he had an admission with COVID-19 pneumonitis requiring 8 days of continuous positive airway pressure. He was tachypnoeic with a respiratory rate of 24 breaths/min, oxygen saturations on room air of 91%. Examination revealed reduced air entry and a resonant percussion note over the right hemithorax. Chest radiograph suggested a complex right pneumothorax; however, a CT chest was notable for widespread right-sided bullous lung disease. After a day of observation on a COVID-19 ward (and a repeat radiograph with a stable appearance), he was discharged with a 2-week follow-up with the respiratory team, safety netting advice and ambulatory oxygen. This case suggests that bullous lung disease may be a complication of severe COVID-19 pneumonitis.

Characteristics and Outcomes of Patients Infected with SARS-CoV-2 in Israel: Correlation between Laboratory Findings on Admission to Emergency Department and Subsequent Respiratory Failure.

BACKGROUND: There is limited clinical information on coronavirus disease-19 (COVID-19) patients in Israel. OBJECTIVES: To describe the characteristics, outcomes, and potential associations of hospitalized COVID-19 patients in Israel. METHODS: We conducted a single-center, retrospective study of 58 consecutive laboratory-confirmed COVID-19 patients admitted to Laniado Hospital, Israel, between 14 March 2020 and 14 May 2020. Demographic, clinical, and laboratory data on admission were collected and analyzed, and the association to subsequent respiratory failure was assessed. RESULTS: Mean age of patients was 70.7 ± 16.9 years (53% males, 47% females.); 74% had at least one co-morbidity. Most patients were of Jewish Ashkenazi descent. During hospitalization 15 patients (mean age 78.18 ± 10.35 years); 80% male, 73% Sephardi descent developed respiratory failure rates of 60% occurring on average 10.6 days following intubation. Laboratory tests at admission displayed a significant increase in C-reactive protein (CRP) and creatine kinase (CK) and a decrease in absolute lymphocyte count (ALC) in patients who eventually developed respiratory failure (163.97 mg/L, 340.87 IU/L, 0.886 K/µl vs. 50.01 mg/L and 123.56 IU/L, 1.28 K/µl, respectively). Multivariate logistic analysis revealed an integrated parameter of CRP, CK, and ALC highly correlated with respiratory failure. Receiver operating characteristic curve revealed the area under the curve of CRP, CK, and ALC and the integrated parameter to be 0.910, 0.784, and 0.754, respectively. CRP was the strongest predictor to correlate with respiratory failure. CONCLUSIONS: CRP, CK, and ALC levels on admission could possibly be used to detect high-risk patients prone to develop respiratory failure.

Severity of respiratory failure at admission and in-hospital mortality in patients with COVID-19: a prospective observational multicentre study.

OBJECTIVES: COVID-19 causes lung parenchymal and endothelial damage that lead to hypoxic acute respiratory failure (hARF). The influence of hARF severity on patients' outcomes is still poorly understood. DESIGN: Observational, prospective, multicentre study. SETTING: Three academic hospitals in Milan (Italy) involving three respiratory high dependency units and three general wards. PARTICIPANTS: Consecutive adult hospitalised patients with a virologically confirmed diagnosis of COVID-19. Patients aged <18 years or unable to provide informed consent were excluded. INTERVENTIONS: Anthropometrical, clinical characteristics and blood biomarkers were assessed within the first 24 hours from admission. hARF was graded as follows: severe (partial pressure of oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) <100 mm Hg); moderate (PaO2/FiO2 101-200 mm Hg); mild (PaO2/FiO2 201-300 mm Hg) and normal (PaO2/FiO2 >300 mm Hg). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the assessment of clinical characteristics and in-hospital mortality based on the severity of respiratory failure. Secondary outcomes were intubation rate and application of continuous positive airway pressure during hospital stay. RESULTS: 412 patients were enrolled (280 males, 68%). Median (IQR) age was 66 (55-76) years with a PaO2/FiO2 at admission of 262 (140-343) mm Hg. 50.2% had a cardiovascular disease. Prevalence of mild, moderate and severe hARF was 24.4%, 21.9% and 15.5%, respectively. In-hospital mortality proportionally increased with increasing impairment of gas exchange (p<0.001). The only independent risk factors for mortality were age ≥65 years (HR 3.41; 95% CI 2.00 to 5.78, p<0.0001), PaO2/FiO2 ratio ≤200 mm Hg (HR 3.57; 95% CI 2.20 to 5.77, p<0.0001) and respiratory failure at admission (HR 3.58; 95% CI 1.05 to 12.18, p=0.04). CONCLUSIONS: A moderate-to-severe impairment in PaO2/FiO2 was independently associated with a threefold increase in risk of in-hospital mortality. Severity of respiratory failure is useful to identify patients at higher risk of mortality. TRIAL REGISTRATION NUMBER: NCT04307459.

A 63-Year-Old Woman with SARS-CoV-2 Infection, Who Developed Severe COVID-19 Pneumonia and Was Supported with Convalescent Plasma Therapy.

BACKGROUND There is no evidence-based treatment for coronavirus disease 2019 (COVID-19). We report the case of a 63-year-old woman with SARS-CoV-2 infection who developed severe COVID-19 pneumonia and was treated with convalescent plasma. CASE REPORT A 63-year-old woman who presented with severe and prolonged course of COVID-19 disease (fever up to 39.4°C, persistent cough, and dyspnea) received a convalescent plasma transfusion, which led to complete recovery. The diagnosis was confirmed by RT-PCR testing using the CFX96 Real-Time System (Bio-Rad, USA) from nasopharyngeal swabs. In laboratory tests, an increase in acute-phase parameters was observed. Chest computed tomography (CT) showed abnormalities typical for COVID-19. On days 9 and 11 of the disease, she received the convalescent plasma prepared from a single plasmapheresis donation from a male donor. This male donor was qualified as a convalescent plasma donor according to Polish guidelines, which are compliant with European guidelines. He donated plasma at the Regional Centre for Transfusion Medicine in Bialystok, Poland. The therapy with convalescent plasma led to clinical improvement and normalization of inflammatory parameters. CONCLUSIONS This report presents a case of severe COVID-19 pneumonia in a 63-year-old woman who was given supportive treatment with convalescent plasma. Ongoing clinical trials will determine whether convalescent plasma therapy is an effective treatment for SARS-CoV-2 infection.

Inferior Wall Myocardial Infarction in Severe COVID-19 Infection: A Case Report.

BACKGROUND The novel coronavirus disease (COVID-19) has been declared a pandemic. With the ever-increasing number of COVID-19 patients, it is imperative to explore the factors related to the disease to aid patient management until a definitive vaccine is ready, as the disease is not limited to the respiratory system alone. COVID-19 has been associated with various cardiovascular complications including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism. The infection is severe in patients with pre-existing cardiovascular disease, and a systemic inflammatory response due to a cytokine storm in severe COVID-19 cases can lead to acute myocardial infarction. CASE REPORT We present the case of a 56-year-old man with cardiovascular risk factors including coronary artery disease, hypertension, ischemic cardiomyopathy, and hyperlipidemia, who had COVID-19-induced pneumonia complicated with acute respiratory distress syndrome. He subsequently developed myocardial infarction during his hospitalization at our facility. He had a significant contact history for COVID-19. He was managed with emergent cardiac revascularization after COVID-19 was confirmed by real-time reverse transcription-polymerase chain reaction testing from a nasopharyngeal swab as per hospital policy for admitted patients. Apart from dual antiplatelet therapy, tocilizumab therapy was initiated due to the high interleukin-6 levels. His hospitalization was complicated by hemodialysis and failed extubation and intubation, resulting in a tracheostomy. Upon improvement, he was discharged to a long-term facility with a plan for outpatient follow-up. CONCLUSIONS In high-risk patients with COVID-19-induced pneumonia and cardiovascular risk factors, a severe systemic inflammatory response can lead to atherosclerotic plaque rupture, which can manifest as acute coronary syndrome.

A Severe COVID-19 Case Complicated by Right Atrium Thrombus.

BACKGROUND Recent studies demonstrated evidence of coagulation dysfunction in hospitalized patients with severe coronavirus disease 2019 (COVID-19) due to excessive inflammation, hypoxia, platelet activation, endothelial dysfunction, and stasis. Effective anticoagulation therapy may play a dominant role in the management of severe COVID-19 cases. CASE REPORT A 73-year-old man with a 6-day history of fever up to 38.5°C, dyspnea, cough, and fatigue was diagnosed with COVID-19. He had a past medical history significant for hypertension and coronary artery bypass grafting. Two days after hospital admission, the patient developed acute respiratory failure, requiring intubation, mechanical ventilation, and transfer to the intensive care unit (ICU). He received treatment including antibiotics, hydroxychloroquine, tocilizumab, vasopressors, prone positioning, and anticoagulation with enoxaparin at a prophylactic dose. After a 15-day ICU stay, the patient was hemodynamically stable but still hypoxemic; a transthoracic echocardiogram at that time, followed by a transesophageal echocardiogram for better evaluation, revealed the presence of a right atrium thrombus without signs of acute right ventricular dilatation and impaired systolic function. Since the patient was hemodynamically stable, we decided to treat him with conventional anticoagulation under close monitoring for signs of hemodynamic deterioration; thus, the prophylactic dose of enoxaparin was replaced by therapeutic dosing, which was a key component of the patient's successful outcome. Over the next few days he showed significant clinical improvement. The follow-up transesophageal echocardiogram 3 weeks after effective therapeutic anticoagulation revealed no signs of right heart thrombus. CONCLUSIONS The presented COVID-19 case, one of the first reported cases with evidence of right heart thrombus by transesophageal echocardiography, highlights the central role of diagnostic imaging strategies and the importance of adequate anticoagulation therapy in the management of severe COVID-19 cases in the ICU.

The global response to the COVID-19 pandemic: how have immunology societies contributed?

The COVID-19 pandemic is shining a spotlight on the field of immunology like never before. To appreciate the diverse ways in which immunologists have contributed, Nature Reviews Immunology invited the president of the International Union of Immunological Societies and the presidents of 15 other national immunology societies to discuss how they and their members responded following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).